Cancer is still one of major causes of death even in today's advanced medicine. Cancer cells cannot be fully removed even by treatment with anticancer agents and/or radiotherapy. Even after tumor was removed by surgery, cancer cells remain in patients with advanced cancer having metastatic foci.
Immunosuppressive substances are possible candidates which prevent the cancer cells from being perfectly removed. Living bodies inherently should have immune functions such as cancer specific killer cells that eliminate cancerous cells. It is conceived that some of immunosuppressive substances are present in the blood of healthy subjects and play a role for controlling immune actions, but some abnormally grow along with the advance of cancer, prevent the induction and expression of the functions of the cancer specific killer cells to thereby suppress the immune functions against the cancer cells and, as a result, assist the growth of the cancer cells.
Known immunosuppressive substances are immunosuppressive proteins such as transforming growth factor beta (subtypes 1 to 5 are known, and they are hereinafter briefly and generically referred to as “TGF β”), immunosuppressive acidic protein, carcinoembryonic antigens, interleukin 6 and tumor necrosis factors (TNFs); prostaglandin E2; and cells such as B cells and macrophages (Hiromi Fujiwara, Tumor Immunology, p. 89-112, Chugai Igaku-sha Ltd., 1998).
Accordingly, removal of immunosuppressive substances holds promise of increasing the immunity of a patient, suppressing the growth of cancer cells and leading the tumor to regression.
Attempts have therefore been made to remove or eliminate immunosuppressive substances such as immunosuppressive acidic protein and carcinoembryonic antigens by plasma exchange (see, for example, Non-patent Document 1). Attempts have also been made to remove immunosuppressive substances by using an apparatus comprising a double membrane plasma separator and an adsorbent made from an amino-group-bearing glass beads for adsorbing immunosuppressive factors having low molecular weights. This technique is intended to reduce a displacement liquid (see, for example, Non-patent Document 2). In addition, combined therapy of plasma exchange and an anticancer agent cyclophosphamide has been attempted (see, for example, Non-patent Document 3). These treatments, however, do not work sufficiently effectively. This is probably mainly because the adsorbents have insufficient adsorptivity. In addition, the plasma exchange has a low removing efficiency and brings a risk of infection of a disease from a plasma donor.
As the TGF β adsorbents, one having a hydrophobic ligand has been disclosed (see Patent Document 1). This technique, however, is intended for an “active TGF β” having a molecular weight of about 25,000 as described in the document, and the document fails to describe a “latent TGF β” having a molecular weight of about 10×104 to 30×104. In general, a compound having an increasing molecular weight among compounds of the same type becomes more difficult to be absorbed by an adsorbent.
Techniques for analyzing the active molecules typically by allowing hydroxyapatite to adsorb and/or desorb TGF β1 in the blood have been disclosed (see Patent Documents 2 to 4). These techniques, however, also intended for the active TGF β.
The immunosuppressive acidic protein is a protein having a molecular weight of about 5×104 and is clinically used as a marker for the malignancy of cancer. An attempt has been made to remove the immunosuppressive acidic protein using an active carbon column (see Non-patent Document 4), but has not yet been used in practice, probably because of its insufficient adsorptivity. The active carbon column is not suitable for applications in which it comes in direct contact of the blood, such as extracorporeal perfusion, since the active carbon often yields powders.
Attempts have been made to treat cancer by subjecting the blood to extracorporeal perfusion using a fiber having a lipopolysaccharide of a gram-negative bacterium immobilized thereto to thereby activate the blood (see Non-patent Document 5 and Patent Documents 5 to 9). The lipopolysaccharide serves as an endotoxin. This fiber, however, is not an adsorbent but a cell activator. In addition, these documents do not refer to the adsorption of immunosuppressive substances.
Patent Documents 10 and 11 each disclose a fiber having an immobilized hydrophilic amine. These techniques, however, are intended for the adsorption of endotoxins, do not refer to the adsorption of immunosuppressive substances and are not intended for the treatment of cancer.
[Non-Patent Document 1]    Toge et al., “Significance of Plasma Exchange Treatment in Cancer Treatment”, Biotherapy, vol. 2, 1988, p. 1019-1028
[Non-Patent Document 2]    Kunzo Orita, “Basic and Clinical Researches for Clinical Applications of Double Membrane Plasmapheresis in order to Remove Immunosuppressive Factors in Serum of Patients with Cancer”, Gan Chiryo no Ayumi (in Japanese, “Progress in Cancer Treatment”), vol. 4, 1984, p. 18
[Non-Patent Document 3]    Nishioka et al., “Effects of Membrane Plasma Exchange Treatment on Growth Suppression of Tumor of Tumor-bearing Rat—combined effects with immunochemical therapy—”, Jinko Zoki (in Japanese, “Artificial Organ”), vol. 14, 1985, p. 361-365
[Non-Patent Document 4]    O. Ishiko et al, Removal of Immunosuppressive Substance in Cancer-Patients' Serum, Jpn J Cancer Res, 81, 564-566, (1990)
[Non-Patent Document 5]    T. Tani et al., Efficancy and Biocompatibility of Nobel anti-Cancer Fiber in Hemoperfusion on Cancer-Bearing Rabbits, Therapeutic Apheresis, 6(2), 167-172, (2000)
[Patent Document 1]    Japanese Unexamined Patent Application Publication No. 2001-218840
[Patent Document 2]    Japanese Unexamined Patent Application Publication No. 7-31875
[Patent Document 3]    Japanese Unexamined Patent Application Publication No. 8-193997
[Patent Document 4]    Japanese Unexamined Patent Application Publication No. 9-80042
[Patent Document 5]    Japanese Unexamined Patent Application Publication No. 59-64053
[Patent Document 6]    Japanese Unexamined Patent Application Publication No. 59-211458
[Patent Document 7]    Japanese Unexamined Patent Application Publication No. 60-2258
[Patent Document 8]    Japanese Unexamined Patent Application Publication No. 60-12071
[Patent Document 9]    Japanese Unexamined Patent Application Publication No. 60-89425
[Patent Document 10]    Japanese Unexamined Patent Application Publication No. 60-197703
[Patent Document 11]    Japanese Unexamined Patent Application Publication No. 60-195455